Bismuth nicotinate



Patented Feb. 4, 1941 I UNITEDSTATES PATENT OFFICE BISMUTH NICOTINATEEdwin Dowzard, Brooklyn, N. Y., and Leo A. Flexser, Union City, N. J.,assignors to The New York Quinine & Chemical Works, Inc., Brooklyn, N.Y., a corporation of New York No Drawing. Application October 3, 1939,Serial No. 297,766

4 Claims. (01. 260-270) i This invention or discovery relates to bismuthhot flashes. In any event, administration of nicotinates; and itcomprises, as a new and valnicotinic acid as such, or in the form of itssalts, uable therapeutic material, a preparation compresents to thestomach a concentrated preparaprising a bismuth nicotinate of acomposition tion in which the nicotinic acid is rapidly avail- 5 rangingbetween Bi(OH)2R and Bi(OI-I)R2, able. As stated, in all natural foodswhere nic- 5 where R represents the nicotinic radical otinic acid ispresent it is in low concentration; C5NH4COO, said preparation sometimescomin extremely minute amounts on a percentage prising other bismuthcompounds and said nicbasis. No great amount of readily availablenicotinate being a white pulverulent material only otinic acid everoccurs in normal nutriment. The

0 slightly soluble in water and dilute acids; it physiological activityof nicotinic acid seems to further comprises a method of making such adepend upon the bodies with which it is assopreparation wherein asoluble nictotinate is ciated in foods. Free nicotinic acid is anexbrought into reaction with a bismuth salt and tremely reactive body,having basic functions,

} the product of reaction is washed and dried; and due to the pyridinegroup, aswell as acidity. This it still further comprises such apreparation in may be a reason that in administering it as such 15 dosedform suitable for therapeutic purposes; the contents of the stomach atthe time make a all as more fully hereinafter set forth and asdifference as to results. claimed. It has now been discovered that inadminister- Nicotinic acid is pyridine carboxylic acid, ing nicotinicacid in combination with bismuth,

C5NH-1.COOH; the carboxyl being carried by a or in association withbismuth compounds, these 20 beta carbon of the pyridine ring. It can bemade irregularities of result disappear. In-the bismuth synthetically inmany ways, using as starting nicotinates, the nicotinic acid is slowlyavailable; material various pyridine derivatives carrying an thenicotinate passes into the digestive tract via alkyl or other group on abeta carbon. On oxithe stomach. The nicotinic acid is available butdation the side chain is converted into carboxyl. not rapidly; there isno local production of any 25 Nicotinic acid can be so produced fromnicotine, high concentration of nicotinic acid. whence the name.Nicotinic acid is found in In the administration of nicotinates ofbismuth minute quantities rather generally in vegetable the results arenot afiected by the temporary and animal tissues used for food; and,like the acidity or the temporary contents of the stomach 3o vitamins,it plays an ill-understood but important and digestive system. Thebismuth nicotinates part in nutrition. It quite often accompaniesmetathesize slowly and provide a slow steady the anti-neuritic vitamin Band is a by-product supply of nicotinic acid. The result is more in thecomplicated chemical processes employed n rly h Whe a f containing a smllfracin isolating the extremely small amounts of the tion of a per centof nicotinic acid is con umed Vitamin found in rice polishings. thanthat obtained in direct administrati n of 35 Commercially, however,nicotinic acid is mannicotinic acid or soluble nicotinates. Whateverufactured chemically and is marketed as the free the reason, the regulai y o result in using acid; a white crystalline material. This has muthnicotinate is better, as stated. acquired medical status as a remedy invarious It has further been observed that in clinical deficiencydiseases, notably pellagra. In nicoadministration the results obtainedare not only 40 tinic acid therapy, as in vitamin therapy, exact regularand predictable but are of difierent type dosage and regular results arehighly important. from that which might have been expected from Inpractice, however, it is found that using either the several propertiesof the components united the free nicotinic acid or the solublenicotinates to form bismuth nicotinate.

of the alkali bases, the results are irregular. It is found sometimesworth while to blend 45 The acidity of free nicotinic acid sometimesbismuth nicotinate with the various bismuth subdisturbs the stomach butapart from this, the salts used in medicine; bismuth subnitrate forphysiological reaction to the administration of example. nicotinic acidor of nicotinates is quite variable. From a stoichiometric point of viewbismuth is The particular results depend not only on the trivalent; asin BiCla. The tri salts, however, 50 temporary acidity of the stomachbut also on hydrolyze readily down to the subsalts, such as the natureof the foods present in the digestive bismuth subnitrate, or BiOCl,which are those .act. Probably there are other factors not unmostly usedin medicine. derstoo'd contributing to the irregularity. Some- Bismuthoxide alone has no g ea physiological times there are annoyingpathological symptoms; action because of the insolubility of bismuth 55compounds in the body fluids. However, some bismuth subsalts have beengiven internally to coat irritated parts of the digestive system.Regarded purely as a bismuth compound, the bismuth subnicotinates arebelieved to be better than the bismuth compounds ordinarily used. Thenicotinic acid has a healing effect on irritated tissues; a fact notedin the ordinary administration of nicotinic acid in the early stages ofpellagra.

Certain bismuth preparations have been employed heretofore asintramuscular injections in the treatment of syphilis, and here againthe bismuth nicotinates seem to be superior to the bismuth compoundspreviously available. In these latter, only the bismuth is useful but inbismuth nicotinates both of the constituents are active in some degreein treatments combating spirochetic maladies. 7

To summarize, the bismuth nicotinate preparations of the presentinvention constitute improved therapeuticals for use not only whennicotinic acid is indicated but when bismuth is to be administeredinternally or by injection.

In the present invention, bismuth ni-cotinates are produced with amolecular formula ranging between Bi(OH)2R and Bi(OH)R2; R signifyingthe niootinic radical. All the preparations within this range areuseful. The dinicotinate (Bi.OH.R2) in a dry pulverulent state containsabout 52 per cent nicotinic acid, while the mononicotinate containsabout 33.5 per cent. These preparations may be made in various ways:directly by taking up nicotinic acid with bismuth hydroxide ormetathetically by producing a reaction between a soluble nicotinate,such as sodium nicotinate, and a salt of bismuth, such as thesubnitrate. Or a mixed method may be used, a subsalt being first formed,metathetically, and then treated with nicotinic acid to increase thepercentage of nicotinic acid; by combination or adsorption or both.

In a typical method of making preparations under the presentinvention,-bismuth subnitrate is suspended in hot water containingnicotinic acid in solution. Good proportions are of the order of onepart by weight of the subnitrate to 20 parts of hot water containing onepart of nicotinic acid. After admixture is effected the liquid is keptat a temperature between and 100 C., with frequent stirring. From timeto time samples are withdrawn and assayed for residual free nicotinicacid. When the free nicotinic acid has fallen to the desired residualconcentration the liquid is cooled, filtered and the insoluble bismuthnicotinate thoroughly washed and dried. It is a fine white powder, veryslightly soluble in water and stable in handling and storage. While thecontained nicotinic acid is available in the digestive tract it is notgiven up to water; the compound does not readily hydrolyze. As stated,the percentage of nicotinic acid may go as high as 52 per cent,corresponding to the dinicotinate. Preparations containing lower ratiosof nicotinic acid are also useful, and are often advantageous. Suchpreparations are readily obtained by this method, as by allowing some ofthe subnitrate to be recovered unreacted in the final product. Or, purenicotinate can be made and then directly admixed with abismuth compound,such as subnitrate, in any desired ratio. The mono-nicotinate containsabout 33 per cent nicotinic acid but lower percentages of nicotinic acidare useful. The lower the percentage of nicotinic acid the nearer thepreparation simulates natural conditions. A bismuth compound containingfrom 2 to 10 per cent nicotinic acid is distinctly better as a bismuthpreparation and the nicotinic acid is useful.

One preparation of relatively low nicotinic acid content which has beenfound useful can be made by dissolving about 10 parts nicotinic acid andabout 3 parts sodium hydroxide in 100 parts ofwater; all by weight. ThepI-I is adjusted to '7 by the use of neutralizing agents. To the aqueousliquid is added 10 parts by weight of bulky bismuth subnitrate and themixture is kept at 95 to 100 C. for about two hours. The product isfiltered off, washed and dried. A bismuth subnicotinate constitutesabout 60 per cent of the product.

In lieu of using the bismuth subnitrate stated in the specific examples,bismuth hydroxide may be employed as may other bismuth compounds such asthe nitrate, chloride, sub-chloride, salicylate, acetate, etc. Butbismuth subnitrate is commercially economical and convenient and it doesnot leave the mother liquor ballasted with any great amount of mineralsalts.

Using any of these materials the physical character of the productchanges somewhat. Other variables are temperature, dilution and time.Commercially dense and light forms of bismuth compounds give differentresults. The differences are more physical than chemical, and theconditions can be adjusted to give dense or light products at will. Inall cases, the nicotinic acid is combined with the bismuth in fixedform;

it cannot be washed out by water or extracted by alcohol.

Sometimes in therapeusis a high nicotinic acid content is desired, up tothe 52 per cent of the dinicotinate, but more often a lower nicotinicacid content is desired. Even the mono-nicotinate with 33.5 per centsometimes represents too great a nicotinic acid concentration. Wherethis is the case the preparation may be diluted with bismuth salts;unreacted bismuth compounds left in the manufacture or mechanicallyadmixed bismuth compounds. Very low percentages of nicotinic acid, say 2or 3 per cent, materially improve bismuth compounds and are useful.

The preparations may be dispensed in dosed amounts and in a formsuitable for clinical administration; capsules, pills, sirups, etc.

What is claimed is:

1. As a new and useful therapeutic composition, a bismuth nicotinate.

2. A therapeutic preparation containing bismuth nicotinate.

3. A therapeutic-preparation containing combined bismuth and nicotinicacid with a nicotinic acid content ranging between 10 and 52 per cent.

4. The process of preparing compositions containing bismuth nicotinate,which comprises adding bismuth subnitrate and nicotinic acid to an ampleamount of hot water, maintaining the system at a temperature of about 50to 100 C., with agitation, until the desired combination of bismuth andnicotinic acid is effected, cooling, and separating from the liquid asolid reaction product containing about 10 per cent to 52 per cent ofcombined nicotinic acid.

